Non-cardiac chest pain (NCCP) is a common functional esophageal disorder, with chronic unexplained symptoms without any identified structural disease. The pain is presumed to be of esophageal origin and is characterized by episodes of unexplained pain that are usually midline. The pain is easily confused with cardiac angina or pain from other esophageal disorders. About 15% - 30% of angiograms performed in chest pain patients are normal, and a coronary artery spasm rarely explains the symptoms. In United States, at least 500,000 coronary angiograms are performed annually for chest pain; NCCP may be present in 75,000 to 150,000. Physiologic mechanisms of underlying symptom production are poorly understood. Most of the available clinical information is from the patient that seeks treatment after the development of symptoms. Therefore, for most part the basic mechanisms that initiate the symptoms remain unknown. Often NCCP is associated with long history of acid reflux without development of esophagitis. It is thought that the hypersensitivity in NCCP could be due to sensitization of peripheral and/or central sensory neurons. The major goal of this research proposal is to understand peripheral sensory mechanisms of esophageal pain under normal physiological condition and during acute and chronic acidification of the esophagus. Electrophysiological and pharmacological studies will be undertaken to understand the roles of sensory neurons in pain and attenuation of their responses, respectively. The proposed specific aims involve systematic characterization of responses of vagal and spinal sensory afferent fibers to mechanical, thermal and chemical stimuli before and after acidification. The study will mainly focus to understand the contribution of cationic channels (ASICs, VR1/TRPV1 and CMR1), ionotropic glutamate receptors (NMDA and AMPA) and neurokinin receptors (NK1, NK2 and NK3) in neuroplastic changes of these neurons in acute and chronic acid exposure. The proposed work is a thorough investigation of peripheral mechanism of esophageal hypersensitivity and pain. The study will provide a valuable information about the adequate stimuli and response characteristics of the primary sensory afferent fibers and the manner in which their altered patterns contribute to visceral hyperalgesia and allodynia. Pharmacological study will provide insight in drug development in management of esophageal pain. [unreadable] [unreadable] [unreadable]